Human skin color is genetically determined by the intracutaneous concentration and distribution of melanin, and is also affected by environmental or physiological conditions such as UV rays of the sun, fatigue, and stress.
Many studies have reported on the chemical effects of melanin synthesis. Melanin is produced by an organelle called a melanosome located in melanin-producing cells, melanocytes, and then transferred to keratinocytes. This melanin is known to protect the cells from UV light and is responsible for skin color.
The precursor of the melanin synthesis is an amino acid called tyrosine, which is known to be converted into dihydroxyphenylalanine (DOPA) and then dopaquinone, and finally results in the formation of melanin. Regarding the melanin biosynthesis, tyrosinase (TYR), tyrosine-related protein 1 (TYRP1) and dopachrome tautomerase (DCT) are known to contribute to melanin biosynthesis, and their major transcription factor, microphthalmia-associated transcription factor (MITF), also regulates melanin biosynthesis. Above all, TYR is known to have a critical role in melanin biosynthesis and is required for oxidation of tyrosine to DOPA and of DOPA to dopaquinone, and inhibition of TYR activity will lead to inhibition of melanin synthesis.
Among intrinsic components with a low molecular weight, a sulfhydryl agent containing sulfhydryl groups such as cysteine or reduced glutathione (GSH) has a role as a suppressor of TYR activity.
Meanwhile, the intracellular sulfhydryl agent not only suppresses the TYR activity, but also has an important role in the further metabolism of dopaquinone. Dopaquinone, an intermediate of melanin synthesis, may be converted into cysteinyldopa or glutathionyldopa by conjugation to cysteine or GSH, and their metabolites are converted into pheomelanin. In contrast to eumelanin, which is black or brown, pheomelanin is yellow or red, and a higher pheomelanin to eumelanin synthesis ratio results in yellow or red as the intensity of pigment becomes lower. The ratio of these two melanin pigments is a key factor in creating differences in skin color based on race. Additionally, it is known that reactive oxygen species (ROS), produced due to UV exposure, exhaust the intracellular sulfhydryl agent, thereby suppressing pheomelanin synthesis and promoting conversion into eumelanin.
Resveratrol is known to inhibit melanin synthesis as it suppresses the activity of MITF and TYR promoter in human epidermal melanocytes (Lin C B. et al., J invest Dermatol 2002; 119:1330-40). Accordingly, resveratrol decreases cellular melanin synthesis through multiple mechanisms, including inhibition of catalytic activity, gene expression, and posttranslational maturation of the TYR enzyme. Due to such effects of resveratrol, various chemical modifications have been attempted in order to enhance the utility of resveratrol.
The stability, safety, and efficacy of active ingredients are considered to be important in the cosmetic industry, but resveratrol is likely to be oxidized, thus making it difficult to be used as a cosmetic component which requires a long shelf life. Recently, the present inventors chemically modified resveratrol to produce resveratryl triacetate (RTA), and reported that the RTA, maintains higher stability to oxidation and is less toxic, compared to resveratrol, using a cultivated melanocytes and a reconstituted skin tissue model, and that it was an effective inhibitor of melanin synthesis, (Park J. et al., Arch Dermatol Res 2014; 306: 475-87). However, a formulation of a cosmetic or pharmaceutical composition is still difficult due to the solubility issues. The safety, toxicity, and efficacy of various active ingredients including resveratrol require further study.
The present inventors have made extensive efforts to seek an active ingredient having a skin-whitening effect, and as a result, they have confirmed that resveratryl triglycolate, produced by chemically modifying resveratrol, inhibits melanin synthesis, decreases expression levels of TYR, TYRP1, and DCT, and decreases MITF, thereby showing an excellent skin-whitening effect, thus completing the present invention.